title: Adenosine deaminase-deficient mice generated using a two-stage genetic engineering strategy exhibit a combined immunodeficiency.
abstract: Adenosine deaminase (ADA) deficiency in humans leads to a combined immunodeficiency. The mechanisms involved in the lymphoid specificity of the disease are not fully understood due to the inaccessibility of human tissues for detailed analysis and the absence of an adequate animal model for the disease. We report the use of a two-stage genetic engineering strategy to generate ADA-deficient mice that retain many features associated with ADA deficiency in humans, including a combined immunodeficiency. Severe T and B cell lymphopenia was accompanied by a pronounced accumulation of 2'-deoxyadenosine and dATP in the thymus and spleen, and a marked inhibition of S-adenosylhomocysteine hydrolase in these organs. Accumulation of adenosine was widespread among all tissues examined. ADA-deficient mice also exhibited severe pulmonary insufficiency, bone abnormalities, and kidney pathogenesis. These mice have provided in vivo information into the metabolic basis for the immune phenotype associated with ADA deficiency.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: S K
authors.initials: SK
authors.lastname: Datta
authors.forename: R E
authors.initials: RE
authors.lastname: Kellems
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics; D043383:Adenosylhomocysteinase; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000943:Antigens, Differentiation; D001402:B-Lymphocytes / Q000166:cytology; D001842:Bone and Bones / Q000002:abnormalities; D003839:Deoxyadenosines / Q000378:metabolism; D005818:Genetic Engineering / Q000379:methods; D006867:Hydrolases / Q000032:analysis; D007668:Kidney / Q000002:abnormalities; D008168:Lung / Q000473:pathology; D018655:Lymphocyte Count; D008231:Lymphopenia; D051379:Mice; D011665:Pulmonary Valve Insufficiency; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012107:Research Design; D016511:Severe Combined Immunodeficiency / Q000201:enzymology / Q000235:genetics*; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology; D013950:Thymus Gland / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D003839:Deoxyadenosines; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000243:Adenosine Deaminase; D000241:Adenosine; C058118:2'-deoxyadenosine